The goal of this clinical research study is to learn if the study drug, alisertib (MLN8237), in combination with chemotherapy (paclitaxel), can shrink or slow tumor growth in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative or HR-negative, HER2-negative (triple negative) locally recurrent or metastatic breast cancer (MBC). The safety of alisertib in combination with paclitaxel will also be studied. The physical state of the patient, symptoms, changes in the size of the tumor, and laboratory findings obtained while on-study will help the research team decide if alisertib plus paclitaxel is safe and effective in patients with this type of breast cancer.

Alisertib belongs to a group of drugs called Aurora kinase inhibitors. Alisertib blocks the activity of Aurora A kinase, a protein that is involved in tumor cell multiplication and survival. Aurora A kinase is expressed at higher than normal levels in many types of cancer, including breast cancer, and preclinical studies suggest that blocking the activity of this protein can lead to the death of cancer cells.

Paclitaxel is a chemotherapy drug commonly used to treat many different kinds of cancer, including metastatic breast cancer. The reason to combine alisertib and paclitaxel is that in cancer therapy, combinations of drugs are often more effective as a treatment than either of the same drugs used alone.

The rationale behind assessing the effectiveness of the addition of alisertib to weekly paclitaxel therapy in patients with Triple Negative Breast Cancer and highly proliferative estrogen receptor-positive (ER+) and HER2- breast cancer is based on the unmet clinical need for effective strategies to prevent or delay resistance to taxane therapy in the metastatic setting. Synergistic or additive effects have been observed in breast cancer xenograft models which involved alisertib added to either paclitaxel or docetaxel. Alisertib inhibited the Pgp-mediated efflux of paclitaxel in a cell culture model. In addition, Aurora Kinase A is frequently overexpressed in Triple Negative Breast Cancer (TNBC), and expression levels have been shown to be prognostic in both of these breast cancer subtypes. The combination of alisertib with paclitaxel has also been investigated in a Phase 1 study in patients with locally advanced or metastatic ovarian and breast cancers, with preliminary evidence of activity in both tumor types including 6 partial response (PR)s and 3 stable disease (SD) in 11 patients with metastatic breast cancer.

Inclusion Criteria:

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care, and signed Health Insurance Portability and Accountability Act (HIPAA) form.

• Female subject (≥18 years old), who is either:

  • post-menopausal for at least one year before the screening visit, or
  • surgically sterilized, or
  • willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide) for the duration of the study.

• Metastatic or locally recurrent breast cancer with histologic confirmation (on either primary or metastatic tumor) of one of the following:

  • ER+, HER2- invasive breast cancer (any progesterone receptor [PgR] status)
  • Poorly differentiated and/or Grade 3 invasive TNBC, defined as:
  • HER2 negative status (based on most recently analyzed biopsy) is defined as immunohistochemistry (IHC) status of 0, 1+ or 2+ (if IHC 2+, a negative FISH test is required, i.e., HER2 fluorescence in situ hybridization (FISH) ratio < 2.0 with an average HER2 copy number <4.0 signals/cell); ER-negative and PR-negative status is defined as ER and PgR <1% nuclei positive by IHC

• Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) (v1.1) or non-measurable lytic, bone-only disease (mixed blastic/lytic bone disease is allowed); if patient has bone-predominant disease with no measurable disease, there must be a lytic component to the bone metastases that is visible on plain X-ray or CT scan that can be serially followed

• Absolute neutrophil count (ANC) > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values must be obtained without need for myeloid growth factor or platelet transfusion support within 14 days, however, erythrocyte growth factor is allowed as per published American Society of Clinical Oncology (ASCO) guidelines (available at: http://www.asco.org/quality-guidelines/asco-ash-clinical-practice-guideline-update-use-epoetin-and-darbepoetin-adult).

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN), serum glutamic-oxaloacetic transaminase (SGOT) (AST) and serum glutamic-pyruvic transaminase (SGPT) (ALT) < 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if patient has known liver metastases

• Adequate renal function as defined by: Calculated creatinine clearance must be ≥ 30 mL/minute (see Cockcroft-Gault formula in Appendix 5)

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (refer to Appendix 4)

Exclusion Criteria:

• Previous radiation therapy covering the whole pelvis

• Suspected brain metastases, untreated brain metastases or current clinical or radiologic progression of known brain metastases or requirement for steroid therapy for brain metastases

  • Patients with treated brain metastases are eligible if they have been stable and off steroids for ≥ 3 weeks

• Prior allogeneic bone marrow or organ transplantation

• Known GI disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease

• Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen.

• Requirement for administration of proton pump inhibitor, or for constant administration of H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed as described in Section 3.4.

• Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Appendix 3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening, within 72 hours prior to first dose of study drug(s). Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Patient has received an investigational agent within 30 days before enrollment

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Other severe acute or chronic medical and/or psychiatric condition(s), including but not limited to uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormalities that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient not eligible for enrollment for this study.

• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, or an in situ malignancy, or a stage I cancer with a 5-year Disease Free Survival (DFS) of ≥ 90% (survival rates by stage are available for most cancers on the American Cancer Society website).

• Treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib and during the study.

• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. Testing is not required in the absence of clinical findings or suspicion. For guidance in defining active infection for hepatitis B, please refer to the World Health Organization (WHO) guidelines, Global Alert and Response (GAR), Hepatitis B. http://who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index4.html)

• Prior administration of an Aurora A kinase-targeted agent, including alisertib

• Need for ongoing therapeutic steroid therapy. Intermittent steroid use for the control of nausea and vomiting is allowed. Premedication with dexamethasone prior to paclitaxel administration is allowed. Topical steroid use is permitted. Inhaled steroids are permitted. Replacement doses of hydrocortisone up to 15 mg/day are allowed.

• Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to alisertib.

• Administration of myeloid growth factors or platelet transfusion within 14 days prior to the first dose of study treatment.

• More than 1 previous chemotherapy regimen for metastatic disease

  • No limit on previous endocrine therapy
  • Previous mammalian target of rapamycin (mTOR) therapy, e.g., everolimus, is allowed
  • Prior adjuvant taxane therapy is allowed, provided the disease-free interval from the end of (neo)adjuvant chemotherapy to the development of metastatic disease was ≥ 1 year
  • No prior taxane for metastatic disease

• Peripheral neuropathy > grade 1

• Known severe hypersensitivity to paclitaxel

174 participants were consented and included in baseline analysis. However, 5 of these did not start study treatment due to ineligibility, participant withdrawal, and/or investigator decision, so only 169 participants were included in Participant Flow and Adverse Event/Serious Adverse Event (AE/SAE) Analysis.

until 30 days after last dose of patient's study treatment, for up to 2 years from date of registration (enrollment into study). However, mortality data was collected for up to 4 years from date of registration.

174 participants consented to study treatment, were randomized and were included in Overall Survival and All-Cause Mortality analysis. However, 5 of these participants did not start study treatment, so only 169 participants were included in AE/SAE Analysis and Participant Flow.

This study has some limitations. First, poor accrual to the TN MBC cohort, likely owing to paclitaxel alone control arm, precludes reliable interpretation of the limited data obtained in this trial. In addition, ER-positive, ERBB2-negative MBC is a heterogeneous disease, and this study does not provide insight into how to identify patients who may benefit from adding alisertib to paclitaxel, as well as those who may not benefit.